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Transancestral mapping and genetic load in systemic lupus erythematosus

2017; Nature Portfolio; Volume: 8; Issue: 1 Linguagem: Inglês

10.1038/ncomms16021

2041-1723

Carl D. Langefeld, Hannah C. Ainsworth, Deborah S. Cunninghame Graham, Jennifer A. Kelly, Mary E. Comeau, Miranda C. Marion, Timothy D. Howard, Paula S. Ramos, Jennifer A. Croker, David Morris, Johanna K. Sandling, Jonas Carlsson Almlöf, Eduardo M. Acevedo‐Vásquez, Graciela S. Alarcón, Alejandra Babini, Vicente Baca, Anders Bengtsson, Guillermo Berbotto, Marc Bijl, Elizabeth E. Brown, Hermine I. Brunner, Mario H. Cardiel, Luís J. Catoggio, Ricard Cervera, Jorge M. Cucho‐Venegas, Solbritt Rantapää‐Dahlqvist, Sandra D’Alfonso, Berta Martins da Silva, Iñigo de la Rúa Figueroa, Andrea Doria, Jeffrey C. Edberg, Emöke Endreffy, Jorge Antonio Esquivel‐Valerio, Paul R. Fortin, Barry I. Freedman, Johan Frostegård, Mercedes García, Ignacio García‐De La Torre, Gary S. Gilkeson, Dafna D. Gladman, Iva Gunnarsson, Joel M. Guthridge, Jennifer Huggins, Judith A. James, Cees G. M. Kallenberg, Diane L. Kamen, David R. Karp, Kenneth M. Kaufman, Leah C. Kottyan, László Kovács, Helle Laustrup, Bernard Lauwerys, Quan‐Zhen Li, Marco A. Maradiaga‐Ceceña, Javier Martı́n, Joseph M. McCune, David R. McWilliams, Joan T. Merrill, Pedro C. Miranda, J. F. Moctezuma, Swapan K. Nath, Timothy B. Niewold, Lorena Orozco, Norberto Ortego‐Centeno, Michelle Petri, Christian A. Pineau, Bernardo A. Pons‐Estel, Janet Pope, Prithvi Raj, Rosalind Ramsey‐Goldman, John D. Reveille, Laurie Russell, José Mario Sabio, Carlos A. Aguilar‐Salinas, Hugo R. Scherbarth, R Scorza, Michael F. Seldin, Christopher Sjöwall, Elisabet Svenungsson, Susan D. Thompson, Sergio Toloza, Lennart Truedsson, Teresa Tusié‐Luna, Carlos Vasconcelos, Luis M. Vilá, Daniel J. Wallace, Michael H. Weisman, Joan Wither, Tushar Bhangale, Jorge R. Oksenberg, John D. Rioux, Peter K. Gregersen, Ann‐Christine Syvänen, Lars Rönnblom, Lindsey A. Criswell, Chaim O. Jacob, Kathy L. Sivils, Betty P. Tsao, Laura E. Schanberg, Timothy W. Behrens, Earl D. Silverman, Marta E. Alarcón‐Riquelme, Robert P. Kimberly, John B. Harley, Edward K. Wakeland, Robert Graham, Patrick M. Gaffney, Timothy J. Vyse,

Monoclonal and Polyclonal Antibodies Research

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.